The prevalence of metabolic diseases such as insulin resistance, diabetes and obesity are reaching epidemic proportions in the US. Physical inactivity and overnutrition are major contributors to these conditions. An increased understanding of how physical activity and fuel supply links skeletal muscle with whole body metabolism is likely to yield important mechanistic insights into metabolic disease and to contribute to the development of novel therapeutic strategies. Calcium signaling in skeletal muscle is critical for muscle contraction, metabolism, and gene expression. The role of calcium entry has been offered as a mechanism for controlling long-term signaling events such as limiting fatigue during exercise. Our research centers on the role of stromal interaction molecule 1 (STIM1), a calcium sensor required for store-operated calcium entry (SOCE), as a key regulator of skeletal muscle calcium signaling. Our current program is focused on the role of STIM1 in oxidative metabolism. Our preliminary data demonstrate that loss of STIM1 alters oxidative metabolism and impairs muscle performance. Here, we will establish the specific changes in metabolism produced by changes in STIM1 signaling and establish the mechanisms through which STIM1 influences muscle metabolism. Specific Aims proposed in this application include: to determine how STIM1 regulates metabolic flexibility; to determine how STIM1 regulates mitochondrial calcium signaling and function; and to determine whether MAP4K4 regulates STIM1 signaling and skeletal muscle metabolism. We will use methodologies that include genetically modified mouse models of STIM1, high resolution calcium imaging, bioenergetics, and metabolomics to address these aims. The studies we propose may provide novel insight to the role of calcium in regulating the metabolic flexibility of skeletal muscle and are likely to have significant implications for the treatment of impaired muscle metabolism associated with diabetes mellitus and other metabolic diseases.